Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol

Sonia M S Espirito Santo, Nuno M M Pires, Lianne S M Boesten, Gery Gerritsen, Niels Bovenschen, Ko Willems Van Dijk, J. Wouter Jukema, Hans M G Princen, André Bensadoun, Wei Ping Li, Joachim Herz, Louis M. Havekes, Bart J M Van Vlijmen

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29 Scopus citations

Abstract

The low-density lipoprotein (LDL) receptor-related protein (LRP) has a well-established role in the hepatic removal of atherogenic apolipoprotein E (APOE)-rich remnant lipoproteins from plasma. In addition, LRP recognizes multiple distinct pro- and antiatherogenic ligands in vitro. Here, we investigated the role of hepatic LRP in atherogenesis independent of its role in removal of APOE-rich remnant lipoproteins. Mice that allow inducible inactivation of hepatic LRP were combined with LDL receptor and APOE double-deficient mice (MX1Cre+LRPflox/floxLDLR -/-APOE-/- On an LDLR-/-APOE-/- background, hepatic LRP deficiency resulted in decreased plasma cholesterol and triglycerides (cholesterol: 17.1 ± 5.2 vs 23.4 ± 6.3 mM, P = . 025; triglycerides: 1.1 ± 0.5 vs 2.2 ± 0.8 mM, P = .002, for MX1Cre+LRPflox/flox-LDLR-/-APOE-/- and control LRPflox/flox-LDLR-/-APOE-/- mice, respectively). Lower plasma cholesterol in MX1Cre+LRP flox/flox-LDLR-/-APOE-/- mice coincided with increased plasma lipoprotein lipase (71.2 ± 7.5 vs 19.1 ± 2.4 ng/ml, P = .002), coagulation factor VIII (4.4 ± 1.1 vs 1.9 ± 0.5 U/mL, P = .001), von Willebrand factor (2.8 ± 0.6 vs 1.4 ± 0.3 U/mL, P = .001), and tissue-type plasminogen activator (1.7 ± 0.7 vs 0.9 ± 0.5 ng/ml, P = .008) compared with controls. Strikingly, MX1Cre +-LRPflox/floxLDLR-/-APOE-/- mice showed a 2-fold higher atherosclerotic lesion area compared with controls (408. 5 ± 115.1 vs 219.1 ± 86.0 103μm2, P = .003). Our data indicate that hepatic LRP plays a clear protective role in atherogenesis independent of plasma cholesterol, possibly due to maintaining low levels of its proatherogenic ligands.

Original languageEnglish (US)
Pages (from-to)3777-3782
Number of pages6
JournalBlood
Volume103
Issue number10
DOIs
StatePublished - May 15 2004

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Espirito Santo, S. M. S., Pires, N. M. M., Boesten, L. S. M., Gerritsen, G., Bovenschen, N., Van Dijk, K. W., Jukema, J. W., Princen, H. M. G., Bensadoun, A., Li, W. P., Herz, J., Havekes, L. M., & Van Vlijmen, B. J. M. (2004). Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol. Blood, 103(10), 3777-3782. https://doi.org/10.1182/blood-2003-11-4051